High-yielding synthesis of N-triazolyl carboxamides via palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1016/j.tet.2017.10.017

Aminocarbonylation of alkenyl and aryl iodides in the presence of 4-amino-4H-1,2,4-triazole as N-nucleophile was carried out in the presence of palladium catalysts. Both types of substrates have shown high chemoselectivity toward carboxamides, i.e. practi

Full text of DOI:10.1016/j.tet.2017.10.017

Accepted Manuscript
High-yielding synthesis of N-triazolyl carboxamides via palladium-catalysed
aminocarbonylation
Máté Gergely, Borbála Boros, László Kollár
PII:
S0040-4020(17)31033-5
10.1016/j.tet.2017.10.017
TET 29020
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 July 2017
Revised Date: 22 September 2017
Accepted Date: 9 October 2017
Please cite this article as: Gergely Máé, Boros Borbá, Kollár Láó, High-yielding synthesis of N-
triazolyl carboxamides via palladium-catalysed aminocarbonylation, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.10.017.
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ACCEPTED MANUSCRIPT
High-yielding synthesis of N-triazolyl carboxamides via palladium-catalysed aminocarbonylation
M. Gergely, B. Boros and L. Kollár*
Graphical abstract
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ACCEPTED MANUSCRIPT
High-yielding synthesis of N-triazolyl carboxamides via palladium-catalysed
aminocarbonylation
Máté Gergely,a Borbála Borosb and László Kollár a,c,*
a) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@gamma.ttk.pte.hu
b) Department of Analytical and Environmental Chemistry, University of Pécs
c) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary
Abstract: Aminocarbonylation of alkenyl and aryl iodides in the presence of 4-amino-
4H-1,2,4-triazole as N-nucleophile was carried out in the presence of palladium
catalysts. Both types of substrates have shown high chemoselectivity toward
carboxamides, i.e. practically no double carbon monoxide insertion resulting in 2-
ketocarboxamides took place. The results have been rationalised on the basis of
mechanistic aspects of aminocarbonylation.
Keywords: carbonylation, palladium, triazole, carbon monoxide, carboxamide
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1. Introduction
Triazoles are among the most investigated heterocycles due to their synthetic and biological
(pharmaceutical) significance.1 It has been further improved by the discovery of the copper-catalysed azide-
alkyne cycloaddition (CuAAC)2 which provides a facile methodology for the synthesis of the 1,2,3-triazole
ring under ambient conditions. In addition to conventional synthesis, this reaction gained a wide application in
bioconjugation 3 and supramolecular chemistry.4
In spite of using 4-amino-1,2,4-triazole derivatives in mesomorphism studies5 and 5-amino-1,3,4-
triazole based compounds in biological investigations,6 sporadic results were published on the use of
aminotriazoles as building blocks. The reaction of an aminotriazole, a carbonyl compound and an alkene-
nitrile provided triazolo-pyrimidines possessing a diverse range in biological activities in efficient synthesis.7
Furthermore, aminotriazole linkers played a key-role in the synthesis of coordination polymers with narrow
pores.8 Materials with non-linear optical response were also obtained using aminotriazoles.9 1,2,4-Triazole-
based compounds of pharmacological importance, such as highly selective aromatase inhibitors10 and
compounds with significant antimicrobial action11 were also synthesised (Figure 1).
Figure 1. Aminotriazole-based compounds of practical importance.
Not only the high-yielding synthesis of novel triazoles but the aim of getting a deeper insight into
structure-reactivity relation in aminocarbonylation, prompted us to investigate N-aminotriazole derivatives as
N-nucleophiles in aminocarbonylation. Our approach is based on the application of palladium-catalysed
aminocarbonylation of iodoalkenes and iodoarenes.12,13
2. Results and discussion
2.1. Aminocarbonylation of iodoalkenes (1-4) in the presence of aminotriazole N-nucleophiles
1-Iodocyclohexene (1), 4-tert-butyl-1-iodocyclohexene (2), 17-iodoandrost-16-ene (3) and 17-iodo-3-
methoxyestra-1,3,5(10),16-tetraene (4) were aminocarbonylated in the presence of palladium catalysts formed
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in situ by the reaction of palladium(II) acetate and triphenylphosphine.14 4-Amino-4H-1,2,4-triazole (a)
(Scheme 1) was used as N-nucleophile. A slight molar excess (1.2 eq.) of nucleophile to iodoalkene substrate
was used under mild reaction conditions (70 oC, 1 bar CO).
Scheme 1. Aminocarbonylation of iodoalkenes (1-4) in the presence of aminotriazole (a).
The aminocarbonylation of iodoalkenes (1-4) with a resulted in the formation of the corresponding N-
(1,2,4-triazol-4-yl) carboxamide products (1a-4a) in all cases (Scheme 1). All substrates were completely
converted to carboxamides in 24 h. The reaction proved to be perfectly chemoselective, that is, neither double
carbonylation resulting in 2-ketocarboxamides nor side-reactions (e.g. aminolysis of the carbon-iodo bond)
were observed. It has to be noted that in spite of the excellent conversions and chemoselectivities, the isolated
yields are still moderate (54-74%) (Figure 2) due to the difficult separation of nucleophile and catalyst from
the target carboxamides by column chromatography.
Even the increase in carbon monoxide pressure (up to 40 bar) had no influence on the composition of
the reaction mixtures. That is, double carbon monoxide insertion leading to the corresponding 2-
ketocarboxamides (1a’-4a’) as potential products (Figure 3) was not observed.
Figure 2. Carboxamides obtained in aminocarbonylation of 1-4; isolated yields (not optimised) in
brackets (Pd(OAc)2 (0.025 mmol), PPh3 (0.05 mmol), 1-4 (1 mmol), a (1.2 mmol), DMF (10 mL), Et3N (0.5
mL), CO (1 bar), 70 oC).
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Figure 3. The potential 2-ketocarboxamide products might be formed upon double CO insertion.
2.2. Aminocarbonylation of iodoarenes (5-19) in the presence of aminotriazole N-nucleophiles (a-c)
Iodobenzene (5) and its 4-substituted derivatives (6-17) (Scheme 2), 2-methoxyiodobenzene (18), as
well as 2-iodothiophene (19) were reacted with 4-amino-4H-1,2,4-triazole (a) as N-nucleophile in palladium-
catalysed aminocarbonylation under the mild conditions described in 2.1.
Scheme 2. Aminocarbonylation of iodoarenes (5-17) in the presence of aminotriazole (a).
The sulphur-containing aminotriazoles (3-phenyl-4-amino-4H-1,2,4-triazole-5-thiol (b) and 3-phenyl-
4-amino-5-methylthio-4H-1,2,4-triazole (c)) did not show any reactivity under the above carbonylation
conditions (Scheme 3). The coordination of the sulphur donors (as soft Pearson-base) to soft palladium(0) or
palladium(II) (as soft Pearson-acids) might be resulted in a stable, catalytically inactive complex. It has to be
noted that stable palladium(II) complexes (fully characterised including x-ray) were synthesised with the
Schiff-base of 4-amino-2H-1,2,4-triazol-3-thiole.15 In this way, probably even the first steps of the catalytic
cycle (see below), the oxidative addition of the iodoarene to palladium(0) or CO activation by palladium(II))
intermediates is highly unfavourable.
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Scheme 3. Aminocarbonylation of iodobenzene (5) in the presence of sulphur-containing
aminotriazoles (b, c).
Figure 4: Carboxamides obtained in aminocarbonylation of 5-19; isolated yields (not optimised) in
brackets (Pd(OAc)2 (0.025 mmol), PPh3 (0.05 mmol), 1-4 (1 mmol), a (1.2 mmol), DMF (10 mL), Et3N (0.5
mL), CO (1 bar), 70 oC).
o
Carrying out aminocarbonylations under atmospheric carbon monoxide at 70 C in 48 h, the isolated yields
shown in Figure 4 were obtained. Most products were formed in excellent isolated yields (83-98%) when the
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substrates were quantitatively converted. There are a few exceptions: substrates 8, 10 and 18, in these cases 33,
73 and 54% conversion were obtained, respectively, under identical reaction conditions.
Since practically complete conversion of the substrate was necessary to isolate the target compounds as
analytically pure compounds, no information about real reactivity of the substrates was available. Therefore,
three substrates (5, 6 and 17) possessing 4-substituents with substantially different characters (characterised by
Hammett para substituent constant (σp)) were selected. Samples were taken from the reaction mixtures after 2,
6, 12 and 24 h reaction (Fig. 5). 4-Cyano-iodobenzene (17) with an electron withdrawing group in 4-position
(σp= + 0.66) proved to be the most reactive providing practically pefect coversion in 6 h (at 1 bar CO pressure)
and in 12 h (at 40 bar CO). 4-tert-Butyliodobenzene (6) with an electron releasing group (σp = -0.20) the less
reactive among the above three iodoaromatics providing only 76% (1 bar) and 32% (40 bar) conversion in 6 h.
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Figure 5. Conversion of aminocarbonylation as a function of time using iodoaromatics (5, 6, 17)
(substrate (1 mmol), 4-amino-1,2,4-triazole (1.2 mmol); Pd(OAc)2,(0.025 mmol); PPh3, (0.05 mmol); Et3N
(0.5 mL), DMF (10 mL), 70 oC).
In the light of earlier findings it is quite unexpected that practically no double carbon monoxide
1
13
insertion leading to aryl-2-ketocarboxamides took place. The H and C NMR taken from the crude product
revealed that the signals of the usual minor product (generally observed even under atmospheric CO pressure),
2-ketocarboxamide are completely missing from the spectra. It has to be noted that 2-ketocarboxamide can be
formed as major product under more severe reaction conditions or appropriate choice of the P-ligand.12
The high chemoselectivity can be rationalised on the basis of a generally accepted catalytic cycle (Figure
6). That is, in cycle-A the substrates (5-19) are oxidatively added to the in situ formed palladium(0) complexes
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resulting in an aryl-iodo-palladium(II) complex (A). The coordination of carbon monoxide (B) is followed by
its insertion into the Pd-C bond. The resulted palladium-acyl complex (C) is ready for the coordination of the
amine nucleophile (D) and to react further to palladium-amido-acyl complex (E) via HI abstraction by a base
(B). The reductive elimination leads to the carboxamides (5a-19a) in the product-forming step while the
reactive palladium(0) complex is re-formed.
According to our catalytic investigations, it can be stated that the amido complex (E) possessing a
heteroaryl (4H-1,2,4-triazol-4-yl) substituent on the ‘amide-N’ is reluctant toward inserting a second carbon
monoxide yielding the acyl-carbamoyl-palladium(II) species (F). This catalytic intermediate can be considered
as a key to the formation of the ketocarboxamide type products (5a’-19a’).
5a'-19a'
N N
5a-19a
N
N N
N N
ArC(O)C(O)N
H
N
N
HNC(O)Ar
HN
O
PdLn
O
cycle-B
F
N
N
5-19
Ar
Ar
I
N
PdLn
NH
PdLn
Ar PdI(Ln)
CO
E
A
Ar
O
CO
BH+I-
B
N
cycle-A
N
N
B
I
Pd(CO)(Ln)
Ar
H NH
D
I
PdLn
C
Ar
O
I
PdLn
Ar
O
N N
N
NH2
Figure 6. A simplified catalytic cycle for the aminocarbonylation of iodorenes with 4-amino-4H-1,2,4-
triazole (a) nucleophile.
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Conclusions
Iodoalkenes, synthesised from the corresponding ketones via a hydrazone, underwent palladium-catalysed
aminocarbonylation with aminotriazole resulting in carboxamides exclusively. Various iodoaromatics, mainly
4-substituted iodobenzenes, were transformed to the corresponding carboxamides using a similar
methodology. Surprisingly, no double carbonylation leading to 2-ketocarboxamides with the same N-
nucleophile was observed. This behaviour of the aminotriazole nucleophile is unique since no such a high
chemoselectivity toward carboxamide was observed before using iodo(bromo)aromatics or aryl triflates, their
synthetic surrogates as substrates.
3. Experimental
3.1. General procedures
13
1H and C NMR spectra were recorded in CDCl3 on a Bruker Avance III 500 spectrometer at 500 and
125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to CHCl3 (7.26 and 77.00 ppm for 1H
and 13C, respectively).
Samples of the catalytic reactions were analysed with an HPLC-MS (Agilent LC/MSD Trap XCT Plus)
(electrospray ionizer, eluent: methanol (0.1 v/v% triethylamine). The FT-IR spectra were taken in KBr pellets
using an IMPACT 400 spectrometer (Nicolet) applying a DTGS detector in the region of 400-4000 cm-1, the
resolution was 4 cm-1. The amount of the samples was ca. 0.5 mg.
1-Iodocyclohexene16 (1), 4-tert-butyl-1-iodocyclohexene16 (2), 17-iodoandrost-16-ene17 (3) and 17-iodo-
3-methoxyestra-1,3,5(10),16-tetraene18 (4) were synthesised by the modified Barton-procedure.19
3.2. Aminocarbonylation of iodoalkenes (1-4) and iodoarenes (5-19) in the presence of nucleophiles a-c under
atmospheric carbon monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.2 mg, 0.05 mmol),
iodoalkene (1-4) or iodoarene (5-19) (1 mmol) were dissolved in DMF (10 mL) under argon in a three-necked
flask equipped with a reflux condenser and a balloon on the top. Aminotriazole nucleophile (a, b or c) (1.2
mmol) and triethylamine (0.5 mL) were added. The atmosphere was changed to carbon monoxide. (Caution:
High pressure carbon monoxide should only be used with adequate ventilation (hood) using CO sensors as
o
well.) The reaction was conducted for the given reaction time upon stirring at 70 C. The mixture was then
concentrated and evaporated to dryness. Toluene (15 mL) was added to the residue, the precipitate (product)
was filtered, washed with water on the filter and dried. The off-white powder-like material was dissolved in
methanol, the palladium-black was filtered off and methanol was evaporated.
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3.3. Aminocarbonylation of iodoalkenes (1-4) and iodoarenes (5-19) in the presence of nucleophiles a-c under
high carbon monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.2 mg, 0.05 mmol),
iodoalkene (1-4) or iodoarene (5-19) (1 mmol) and aminotriazole nucleophile (a, b or c) (1.2 mmol) were
dissolved in DMF (10 mL) under argon in a 100 mL stainless steel autoclave. Triethylamine (0.5 mL) was
added and the atmosphere was changed to carbon monoxide. The reaction was conducted for the given
reaction time upon stirring at 70 oC. The work-up of the reaction mixture is identical with that described above
(3.2).
3.4. Characterization of the products
N-(4H-1,2,4-Triazol-4-yl)cyclohex-1-enecarboxamide (1a). Yield: 142.7 mg (74%), white needle crystal,
sublimation point 187–188 °C; [Found: C, 56.11; H, 6.44; N, 29.01%, C9H12N4O requires C, 56.24; H, 6.29;
N, 29.15%]; δH (500 MHz, DMSO) 11.36 (1H, s, NH), 8.64 (2H, s, CH(triazole)), 6.81 (1H, br s, =CH), 2.18–
2.25 (4H, m, CH2), 1.56–1.67 (4H, m, CH2); δC (125.7 MHz, DMSO) 167.2, 144.3, 136.9, 131.0, 25.4, 24.1,
22.0, 21.5. IR (KBr ν (cm-1)) 3111 (NH), 1680 (CON); MS m/z (rel int.): 191 (100, (M-1)-); MS2 (191) m/z
(rel int.): 191 (52, (M-1)-), 68 (100).
4-(tert-Butyl)-N-(4H-1,2,4-triazol-4-yl)cyclohex-1-enecarboxamide (2a). Yield: 133.8 mg (54%), white
powder, sublimation point 195–196 °C; [Found: C, 62.70; H, 8.20; N, 28.31%, C13H20N4O requires C, 62.88;
H, 8.12; N, 28.56%]; δH (500 MHz, CDCl3) 11.34 (1H, br s, NH), 8.09 (2H, s, CH(triazole)), 7.07–7.09 (1H,
m, =CH), 2.61–2.65 (1H, m, 6-CHeqHax), 2.27–2.38 (2H, m, 3-CHeqHax, 6-CHaxHeq), 1.99–2.05 (2H, m, 5-
CHeqHax, 3-CHaxHeq), 1.33-1.36 (1H, m, 4-CH), 1.23 (1H, qd, J = 12.2, 4.9 Hz, 5-CHaxHeq), 0.92 (9H, s, CH3);
δC (125.7 MHz, CDCl3) 166.9, 143.6, 139.3, 130.2, 43.2, 32.2, 27.6, 27.1, 25.4, 23.5. IR (KBr ν (cm-1)) 3112
(NH), 1687 (CON); MS m/z (rel int.): 247 (100, (M-1)-); MS2 (247) m/z (rel int.): 247 (100, (M-1)-), 220 (31),
184 (19), 155 (16), 83 (17).
N-(4H-1,2,4-Triazol-4-yl)androsta-16-ene-17-carboxamide (3a). Yield: 230.6 mg (63 %), pale orange
solid, mp 272–273 °C; [Found: C, 71.23; H, 8.84; N, 16.08%, C22H32N4O requires C, 71.10; H, 8.75; N,
16.20%]; δH (500 MHz, CDCl3) 11.05 (1H, br s, NH), 8.13 (2H, s, CH(triazole)), 6.88 (1H, br s, =CH), 2.34
(1H, ddd, J = 16.9, 6.4, 3.2 Hz, 15-CHeqHax), 2.22-2.25 (1H, m, 12-CHeqHax), 2.08 (1H, ddd, J = 16.8, 11.9,
1.5 Hz, 15-CHaxHeq), 0.79–1.73 (22H, m, skeleton protons), 1.02 (3H, s, 18-CH3), 0.84 (3H, s, 19-CH3); δC
(125.7 MHz, CDCl3) 164.3, 146.7, 143.5, 141.3, 56.4, 55.2, 47.3, 38.5, 36.5, 34.6, 33.8, 32.5, 31.9, 29.0, 28.9,
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26.8, 22.1, 20.6, 16.4, 12.2. IR (KBr ν (cm-1)) 3127(NH), 1690 (CON); MS m/z (rel int.): 367 (100, (M-1)-);
MS2 (367) m/z (rel int.): 367 (100, (M-1)-), 323 (73), 307 (77), 283 (43).
3-Methoxy-N-(4H-1,2,4-triazol-4-yl)estra-16-ene-17-carboxamide (4a). Yield: 252.4 mg (67%), white
solid, mp 269–270 °C; [Found: C, 69.66; H, 6.81; N, 14.56%, C22H26N4O2 requires C, 69.82; H, 6.92; N,
14.80%]; δH (500 MHz, DMSO) 11.48 (1H, s, NH), 8.70 (2H, s, CH(triazole)), 7.16 (1H, d, J = 8.5 Hz, 1-CH),
6.78 (1H, br s, =CH), 6.69 (1H, dd, J = 8.7, 2.6 Hz, 2-CH), 6.63 (1H, d, J = 2.4 Hz, 4-CH), 3.70 (3H, s,
OCH3), 2.82-2.85 (2H, m, 6-CH2), 2.41 (1H, ddd, J = 16.8, 6.3, 3.2 Hz, 15-CHeqHax), 2.16–2.27 (4H, m, 9-CH,
10- and 11-CHeqHax, 15-CHaxHeq), 1.87-1.90 (1H, m, 7-CHeqHax), 1.37–1.66 (5H, m, 8- and 14-CH, 7-,10- and
11-CHaxHeq), 0.95 (3H, s, 18-CH3); δC (125.7 MHz, DMSO) 164.2, 157.6, 146.8, 144.4, 139.8, 137.8, 132.6,
126.3, 114.0, 111.9, 55.6, 55.4, 47.3, 44.2, 37.1, 34.7, 32.1, 29.5, 27.7, 26.5, 16.7. IR (KBr ν (cm-1)): 3124
(NH), 1679 (CON); MS m/z (rel int.): 377 (100, (M-1)-); MS2 (377) m/z (rel int.): 377 (17, (M-1)-), 364 (37),
337 (30), 311 (100), 255 (23), 183 (11), 125 (12).
N-(4H-1,2,4-Triazol-4-yl)benzamide (5a). Yield: 178.4 mg (95%), white solid, mp 242–243 °C; [Found:
C, 57.20; H, 4.41; N, 29.65%, C9H8N4O requires C, 57.44; H, 4.28; N, 29.77%]; δH (500 MHz, DMSO) 12.12
(1H, br s, NH), 8.79 (2H, s, CH(triazole)), 7.96 (2H, d, J = 7.0 Hz, Hortho(Ph)), 7.69 (1H, t, J = 7.3 Hz,
Hpara(Ph)), 7.60 (2H, t, J = 7.6 Hz, Hmeta(Ph)); δC (125.7 MHz, DMSO) 166.2, 144.3, 133.4, 131.3, 129.3,
128.2. IR (KBr ν (cm-1)) 3108 (NH), 1676 (CON); MS m/z (rel int.): 187 (100, (M-1)-); MS2 (187) m/z (rel
int.): 187 (11, (M-1)-), 68 (100).
4-(tert-Butyl)-N-(4H-1,2,4-triazol-4-yl)benzamide (6a). Yield: 236.5 mg (97%), palebrown needle
crystal, mp. 214-215 °C; [Found: C, 56.11; H, 6.44; N, 29.01%, C13H16N4O requires C, 63.92; H, 6.60; N,
22.93%]; δH (500 MHz, DMSO) 12.02 (1H, br s, NH), 8.77 (2H, s, CH(triazole)), 7.90 (2H, d, J = 8.5 Hz,
CH(Ph)), 7.61 (2H, d, J = 8.5 Hz, CH(Ph)), 1.33 (9H, s, CH3); δC (125.7 MHz, DMSO) 166.1, 156.4, 144.3,
128.5, 128.1, 126.1, 35.3, 31.3. IR (KBr ν (cm-1)) 3118 (NH), 1677 (CON); MS m/z (rel int.): 243 (100, (M-1)-
); MS2 (243) m/z (rel int.): 243 (100, (M-1)-), 216 (31), 109 (28), 68 (43).
4-Methyl-N-(4H-1,2,4-triazol-4-yl)benzamide (7a). Yield: 188.6 mg (93%), pale brown crystal, mp 219–
220 °C; [Found: C, 59.34; H, 5.04; N, 27.56%, C10H10N4O requires C, 59.40; H, 4.98; N, 27.71%]; δH (500
MHz, DMSO) 12.02 (1H, s, NH), 8.78 (2H, s, CH(triazole)), 7.86 (2H, d, J = 7.9 Hz, CH(Ph)), 7.40 (2H, d, J
= 7.9 Hz, CH(Ph)), 2.41 (3H, s, CH3); δC (125.7 MHz, DMSO): 166.1, 144.3, 143.6, 129.8, 128.5, 128.2, 21.6.
IR (KBr ν (cm-1)) 3110 (NH), 1678 (CON); MS m/z (rel int.): 201 (100, (M-1)-); MS2 (201) m/z (rel int.): 201
(100, (M-1)-), 68 (25).
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4-Methoxy-N-(4H-1,2,4-triazol-4-yl)benzamide (8a). Yield: 62.9 mg (29%), pale brownpowder, mp 246-
247 °C; [Found: C, 55.21; H, 4.75; N, 25.49%, C10H10N4O2 requires C, 55.04; H, 4.62; N, 25.68%]; δH (500
MHz, DMSO) 11.94 (1H, br s, NH), 8.77 (2H, s, CH(triazole)), 7.94 (2H, d, J = 8.9 Hz, CH(Ph)), 7.12 (2H, d,
J = 8.9 Hz, CH(Ph)), 3.86 (3H, s, OCH3); δC (125.7 MHz, DMSO) 165.7, 163.3, 144.4, 130.2, 123.3, 114.6,
56.0. IR (KBr ν (cm-1)) 3110 (NH), 1678 (CON), 1264 (C-O); MS m/z (rel int.): 217 (100, (M-1)-); MS2 (217)
m/z (rel int.): 217 (54, (M-1)-), 202 (100), 68 (47).
N-(4H-1,2,4-Triazol-4-yl)-[1,1’-biphenyl]-4-carboxamide (9a). Yield: 253.0 mg (96%), pale brown
needle crystal, mp 254–255 °C; [Found: C, 68.02; H, 4.50; N, 21.03%, C15H12N4O requires C, 68.17; H, 4.58;
N, 21.20%]; δH (500 MHz, DMSO) 12.16 (1H, s, NH), 8.81 (2H, s, CH(triazole)), 8.06 (2H, d, J = 8.5 Hz,
CH(Ph)), 7.92 (2H, d, J = 8.5 Hz, CH(Ph)), 7.79 (2H, d, J = 8.5 Hz, CHortho(Ph)), 7.53 (2H, t, J = 7.9 Hz,
CHmeta(Ph)), 7.45 (1H, t, J = 7.3 Hz, CHpara(Ph)); δC (125.7 MHz, DMSO) 165.9, 144.8, 144.3, 139.2, 130.1,
129.6, 129.0, 128.9, 127.5, 127.4. IR (KBr ν (cm-1)) 3116 (NH), 1685 (CON); MS m/z (rel int.): 263 (100, (M-
1)-); MS2 (263) m/z (rel int.): 263 (59), 237 (25), 109 (15), 97 (100).
4-Fluoro-N-(4H-1,2,4-triazol-4-yl)benzamide (10a). Yield: 135.6 mg (66%), brown powder, mp 252–
253 °C; [Found: C, 52.30; H, 3.54; N, 27.03%, C9H7FN4O requires C, 52.43; H, 3.42; N, 27.17%]; δH (500
MHz, DMSO) br s, NH), 8.79 (2H, s, CH(triazole)), 8.04 (2H, dd, JH-H 8.9 Hz, JH-F 5.5 Hz, CH(Ph)), 7.45 (2H,
dd, JH-H 8.9 Hz, JH-F 8.9 Hz, CH(Ph)); δF (470.4 MHz, DMSO) -106.49 (1F, tt, JH-F 8.9, 5.5 Hz, CF(Ph)); δC
(125.7 MHz, DMSO) 165.2, 165.2 (d, JC-F 251.6 Hz), 144.3, 131.1 (d, JC-F 9.1 Hz), 127.9 (d, JC-F 3.6 Hz),
116.4 (d, JC-F 21.8 Hz). IR (KBr ν (cm-1)) 3112 (NH), 1684 (CON), 1241 (CF); MS m/z (rel int.): 205 (100,
(M-1)-); MS2 (205) m/z (rel int.): 205 (100), 68 (59).
4-Chloro-N-(4H-1,2,4-triazol-4-yl)benzamide (11a). Yield: 211.1 mg (95%), pale brown powder, mp
238–239 °C; [Found: C, 48.39; H, 3.23; N, 25.02%, C9H7ClN4O requires C, 48.50; H, 3.17; N, 25.17%]; δH
(500 MHz, DMSO) 12.21 (1H, br s, NH), 8.79 (2H, s, CH(triazole)), 7.97 (2H, d, J = 8.9 Hz, CH(Ph)), 7.69
(2H, d, J = 8.9 Hz, CH(Ph)); δC (125.7 MHz, DMSO) 165.3, 144.2, 138.3, 130.2, 130.1, 129.5. IR (KBr ν (cm-
1)) 3117 (NH), 1687 (CON), 618 (CCl); MS m/z (rel int.): 221 (100, (M-1)-); MS2 (221) m/z (rel int.): 221
(100), 68 (19).
4-Bromo-N-(4H-1,2,4-triazol-4-yl)benzamide (12a). Yield:254.1 mg (95%), pale brown powder, mp
209–210 °C; [Found: C, 40.53; H, 2.54; N, 20.81%, C9H7BrN4O requires C, 40.47; H, 2.64; N, 20.98%]; δH
(500 MHz, DMSO) 12.21 (1H, br s, NH), 8.79 (2H, s, CH(triazole)), 7.90 (2H, d, J = 8.5 Hz, CH(Ph)), 7.83
(2H, d, J = 8.5 Hz, CH(Ph)); δC (125.7 MHz, DMSO) 165.5, 144.2, 132.4, 130.5, 130.3, 127.3. IR (KBr ν (cm-
13

ACCEPTED MANUSCRIPT
1)) 3108 (NH), 1679 (CON), 616 (CBr); MS m/z (rel int.): 265 (100, (M-1)-), 267 (100, (M-1)-); MS2 (265)
m/z (rel int.): 265 (100, M-), 238 (32), 109 (76), 97 (40).
4-((4H-1,2,4-Triazol-4-yl)carbamoyl)benzoic acid (13a). Yield: 215.2 mg (93%), pale brown powder,
mp 222-224 °C; [Found: C, 51.60; H, 3.60; N, 24.00%, C10H8N4O3 requires C, 51.73; H, 3.47; N, 24.13%]; δH
(500 MHz, DMSO) 13.38 (1H, br s, COOH), 12.30 (1H, br s, NH), 8.81 (2H, s, CH(tiazol)), 8.13 (2H, d, J =
8.4 Hz, CH(Ph)), 8.06 (2H, d, J = 8.4 Hz, CH(Ph)); δC (125.7 MHz, DMSO) 167.0, 165.6, 144.2, 135.0, 130.1,
128.5.
Methyl-4-((4H-1,2,4-triazol-4-yl)carbamoyl)benzoate (14a). Yield: 222.0 mg (90%), brown solid, mp
244–245 °C; [Found: C, 53.53; H, 4.24; N, 22.58%, C11H10N4O3 requires C, 53.66; H, 4.09; N, 22.75%]; δH
(500 MHz, DMSO) 12.33 (1H, s, NH), 8.81 (2H, s, CH(triazole)), 8.16 (2H, d, J = 7.6 Hz, CH(Ph)), 8.08 (2H,
d, J = 7.6 Hz, CH(Ph)), 3.92 (3H, s, CH3); δC (125.7 MHz, DMSO) 166.0, 165.5, 144.2, 135.3, 133.7, 130.0,
128.7, 53.0. IR (KBr ν (cm-1)) 3075 (NH), 1737 (COO), 1686 (CON), 1281 (C-O); MS m/z (rel int.): 245 (100,
(M-1)-); MS2 (245) m/z (rel int.): 245 (100, (M-1)-), 219 (17), 160 (5), 109 (10), 69 (15).
4-Acetyl-N-(4H-1,2,4-triazol-4-yl)benzamide (15a). Yield: 191.2 mg (83%), brown powder, mp 227–
228 °C; [Found: C, 57.30; H, 4.51; N, 24.25%, C11H10N4O2 requires C, 57.39; H, 4.38; N, 24.34%]; δH (500
MHz, DMSO) 12.31 (1H, s, NH), 8.82 (2H, s, CH(triazole)), 8.15 (2H, d, J = 8.5 Hz, CH(Ph)), 8.08 (2H, d, J
= 8.5 Hz, CH(Ph)), 2.66 (3H, s, CH3); δC (125.7 MHz, DMSO): 198.1, 165.6, 144.2, 140.3, 135.0, 129.0,
128.6, 27.5. IR (KBr ν (cm-1)) 3123 (NH), 1685 (CON), 1646 (CO); MS m/z (rel int.): 229 (100, (M-1)-); MS2
(229) m/z (rel int.): 227 (10), 202 (7), 158 (5), 109 (9), 68 (100).
N-(4H-1,2,4-Triazol-4-yl)-4-(trifluoromethyl)benzamide (16a). Yield: 251.7 mg (98%), pale brown
powder, mp 270–271 °C; [Found: C, 46.77; H, 2.94; N, 21.67%, C10H7F3N4O requires C, 46.86; H, 2.76; N,
21.87%]; δH (500 MHz, DMSO) 12.38 (1H, s, NH), 8.82 (2H, s, CH(triazole)), 8.16 (2H, d, J = 8.2 Hz,
CH(Ph)), 8.00 (2H, d, J = 8.2 Hz, CH(Ph)); δF (470.4 MHz, DMSO) -61.54 (3F, s, CF3); δC (125.7 MHz,
DMSO): 165.2, 144.1, 135.2, 133.0 (q, JC-F 31.8 Hz), 129.2, 126.3 (q, JC-F 3.6 Hz), 124.2 (q, JC-F 272.5 Hz). IR
(KBr ν (cm-1)) 3120 (NH), 1696 (CON), 1331 (CF); MS m/z (rel int.): 255 (100, (M-1)-); MS2 (255) m/z (rel
int.): 255 (100, (M-1)-), 228 (5), 109 (9).
4-Cyano-N-(4H-1,2,4-triazol-4-yl)benzamide (17a). Yield: 210.0 mg (98%), brown powder, mp 245–246
°C; [Found: C, 56.23; H, 3.40; N, 32.69%, C10H7N5O requires C, 56.34; H, 3.31; N, 32.85%]; δH (500 MHz,
DMSO) 12.39 (1H, s, NH), 8.81 (2H, s, CH(triazole)), 8.10 (4H, s, CH(Ph)); δC (125.7 MHz, DMSO) 165.1,
14

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144.1, 135.4, 133.4, 129.1, 118.5, 115.6. IR (KBr ν (cm-1)) 3128 (NH), 2233 (CN), 1689 (CON); MS m/z (rel
int.): 212 (100, (M-1)-); MS2 (212) m/z (rel int.): 212 (100), 68 (6).
2-Methoxy-N-(4H-1,2,4-triazol-4-yl)benzamide (18a). Yield: 107.0 mg (49%), dark brown powder, mp
231–232 °C; [Found: C, 55.21; H, 4.70; N, 25.54%, C10H10N4O2 requires C, 55.04; H, 4.62; N, 25.68%]; δH
(500 MHz, DMSO) 11.46 (1H, br s, NH), 8.73 (2H, s, CH(triazole)), 7.87 (1H, dd, J = 7.8, 1.7 Hz, CH(Ph)),
7.62 (1H, ddd, J = 8.5, 7.2, 1.8 Hz, CH(Ph)), 7.25 (1H, d, J = 8.5 Hz, CH(Ph)), 7.13 (1H, dd, J = 7.8, 7.2 Hz,
CH(Ph)), 3.95 (3H, s, OCH3); δC (125.7 MHz, DMSO): 165.0, 158.0, 144.4, 134.6, 131.5, 121.2, 119.8, 112.8,
56.5. IR (KBr ν (cm-1)) 3270 (NH--O), 3118 (NH), 1666 (CON), 1252 (C-O); MS m/z (rel int.): 217 (100, (M-
1)-); MS2 (217) m/z (rel int.): 217 (100), 68 (48).
N-(4H-1,2,4-Triazol-4-yl)thiophene-2-carboxamide (19a). Yield: 162.7 mg (84%), pale brown solid, mp
250–251 °C; [Found: C, 43.20; H, 3.31; N, 28.72%, C7H6N4SO requires C, 43.29; H, 3.11; N, 28.85%]; δH
(500 MHz, DMSO) 12.14 (1H, s, NH), 8.80 (2H, s, CH(triazole)), 8.00 (1H, dd, 4.9, 0.9 Hz, CH(thiophene)),
7.93 (1H, d, 3.4 Hz, CH(thiophene), 7.29 (1H, dd, 4.9, 3.7 Hz, CH(thiophene); δC (125.7 MHz, DMSO) 161.1,
144.4, 135.5, 133.8, 131.0, 129.0. IR (KBr ν (cm-1)) 3084 (NH), 1670 (CON); MS m/z (rel int.): 193 (100, (M-
1)-); MS2 (193) m/z (rel int.): 193 (100, (M-1)-), 68 (6).
Acknowledgement: The authors thank the Hungarian Research Fund (K113177) for the financial
support. This work was supported by the GINOP-2.3.2-15-2016-00049 grant. M. G. thanks Talentum Fund of
the Gedeon Richter Chemical Works Ltd. for the scholarship. The present scientific contribution is dedicated
to the 650th anniversary of the foundation of the University of Pécs, Hungary.
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